Impact of the peroxisome proliferator activated receptor-γ coactivator-1β (PGC-1β) Ala203Pro polymorphism on in vivo metabolism, PGC-1β expression and fibre type composition in human skeletal muscle

Abstract

Peroxisome proliferator activated receptor-gamma coactivator-1beta (PGC-1beta, also known as PPARGC1B) expression is reduced in skeletal muscle from patients with type 2 diabetes mellitus and in elderly subjects. Ala203Pro, a common variant in the PGC-1beta gene is associated with obesity. The aim of this study was to investigate whether the PGC-1beta Ala203Pro polymorphism influences the age-related decline in skeletal muscle PGC-1beta expression, in vivo metabolism and markers for muscle fibre type composition. The PGC-1beta Ala203Pro polymorphism was genotyped in 110 young (age 28.0 +/- 1.9 years) and 86 elderly (age 62.4 +/- 2.0 years) twins and related to muscle PGC-1beta expression, in vivo metabolism and markers for fibre type composition. Insulin-stimulated non-oxidative glucose metabolism (NOGM; p = 0.025) and glycolytic flux rate (GF; p = 0.026) were reduced in young Ala/Ala carriers compared with carriers of a 203Pro allele. In addition, a regression analysis, correcting for covariates, showed that the PGC-1beta 203Pro allele was positively related to insulin-stimulated NOGM and GF in the young twins. While muscle expression of PGC-1beta was reduced in elderly compared with young carriers of the Ala/Ala genotype (p < or = 0.001), there was no significant age-related decline in PGC-1beta expression in carriers of the 203Pro allele (p > or = 0.4). However, a regression analysis, correcting for covariates, showed that only age was significantly related to muscle PGC-1beta expression. Finally, PGC-1beta expression correlated positively with markers for oxidative fibres in human muscle. This study suggests that young carriers of a PGC-1beta 203Pro allele have enhanced insulin-stimulated glucose metabolism and may be protected against an age-related decline in PGC-1beta expression in muscle.